PROJECT SUMMARY Multiple human neurological disorders are associated with deficits in social interaction and communication. Although a genetic component of these disorders is well established, their inheritance is complex, and the identification of functional connections between disease loci and impaired behaviors has proven to be extremely difficult. Integration of human genetic studies with studies of animal models will facilitate advances in establishing the comprehensive molecular networks that regulate social behaviors and the identification of gene pathways disrupted in mental disorders. The goals of this project are to dissect specific heritable behaviors segregating in the silver fox (Vulpes vulpes) into discrete interacting components that are understood at the molecular level with the intent of providing valuable insights into the mechanisms underlying a broad range of mammalian interactive social behaviors, including human psychiatric disorders. The specific fox strains developed at the Institute of Cytology and Genetics (ICG) of the Russian Academy of Sciences exhibit markedly different, genetically determined behavioral phenotypes with significant parallels to typical and atypical human behaviors. The current proposal is a joint research project between scientists at the University of Illinois at Urbana-Champaign, the ICG, and the Swedish University of Agricultural Sciences to define the molecular mechanisms underlying these behavioral phenotypes. To investigate the genetics of these behaviors we will 1) identify and compare the genetic architecture of aggressive, anxiety-related, and affiliative behaviors in foxes and 2) fine map fox behavioral loci and define candidate genes and molecular pathways involved in the regulation of these behaviors. The identification of loci and genes influencing social behavior in foxes is expected to provide new insights into, and candidate genes for, human disorders of social behavior. Furthermore, such a well-established large animal model, intermediate to rodents and primates in biological complexity, can serve as a bridge between humans and rodents for molecular studies of behavior, thereby leading to the development of potential therapies. !